1. Field of the Invention
The present invention relates to cosmetic or dermatological preparations containing active substances for the care and protection of the skin, in particular sensitive skin, as well as skin aged or aging through intrinsic and/or extrinsic factors and the use of such active substances and combinations of such substances in the field of cosmetic and dermatological skin care.
2. Discussion of Background Information
Cosmetic skin care is primarily understood as meaning that the natural function of the skin as a barrier against environmental influences (e.g. dirt, chemicals, micro-organisms) and against the loss of substances intrinsic to the body (e.g. water, natural fats, electrolytes) is strengthened or restored. Impairment of this function may lead to increased absorption of toxic or allergenic substances or to attack by microorganisms, resulting in toxic or allergic skin reactions.
For example, in the case of aged skin, a regenerative restoration occurs slowly, whereby in particular the capacity of the horny layer of the epidermis to bind water diminishes. For this reason, the skin becomes inflexible, dry, and cracked (“physiologically” dry skin). The consequence is a barrier damage. The skin becomes susceptible to negative environmental influences, such as the invasion of microorganisms, toxins, and allergens, possibly resulting in even toxic or allergic skin reactions.
In the case of pathologically dry and sensitive skin, barrier damage exists a priori. Epidermal intercellular lipids become deficient or develop in an inadequate quantity or composition. The consequence is an increased permeability of the horny layer and an inadequate protection of the skin against loss of hygroscopic substances and water.
The barrier effect of the skin can be quantified by determining the transepidermal water loss (TEWL). This process involves the evaporation of water from the interior of the body without including the loss of water during perspiration. The determination of the TEWL value has proven to be extremely informative, and may be used for diagnosing cracked or chapped skin, for determining the compatibility of chemically differently composed surfactants and the like.
For the beauty and well-cared appearance of the skin, the proportion of water in the uppermost skin layer is of greatest importance. It is possible to influence the proportion of water favorably and to a limited extent by introducing moisture regulators.
Anionic surfactants, which are in general ingredients of cleansing preparations, are capable of increasing the pH value in the horny layer in a long-lasting manner, which greatly impedes regenerative processes that serve to restore or renew the barrier function of the skin. In this instance, a new, often very unfavorable state of equilibrium develops in the horny layer between regeneration and loss of essential substances as a result of regular extraction. This state of equilibrium decisively affects the outer appearance of the skin and the physiological functioning of the horny layer.
A simple water bath alone without the addition of surfactants causes an initial swelling of the horny layer of the skin, with the degree of this swelling being dependent, e.g., on the duration of the bath and its temperature. At the same time, not only water-soluble substances, for example, water-soluble dirt particles, but also skin-inherent substances, which are responsible for the capacity of the horny layer to bind water, are rinsed off or washed away. In addition, skin-inherent, surface-active substances also cause skin fats to be separated and washed away to a certain extent. After an initial swelling, this causes a subsequent, distinct drying of the skin, which may be increased further by detergent additives.
In the case of healthy skin, these processes are in general irrelevant, since the protective mechanisms of the skin are easily capable of compensating for such slight disturbances of the upper layers of the skin. However, the protective mechanism of the skin surface becomes disrupted already in the case of nonpathological deviations from the normal state, for example, by environmentally caused damage from wear, or irritations, light damage, aged skin, etc. The protective mechanism of the skin may then possibly no longer be capable of fulfilling its function, and needs to be regenerated by external measures.
Moreover, it is known that lipid composition and lipid quantity of the horny layer of the pathologically altered, dry skin and of the dry but not yet diseased skin of younger and older people deviate from the normal condition which is found in the healthy, normally hydrated skin of a same age group. In this regard, changes in the lipid pattern of the very dry, non-eczematous skin of patients with an atopic eczema represent an extreme case of the deviations which are found in the dry skin of people with healthy skin.
In addition to cholesterol, these deviations relate quite particularly to ceramides which are greatly reduced in their quantity and, in addition, differently composed. In this regard, the deficit of ceramides 1 and 3 is particularly striking, it being known in particular in the case of ceramide 1 that it increases in a special way the order of the lipids in the intercellular membrane systems.
Disadvantageous changes in the lipid membranes of the kind described above are possibly based on a dysregulated lipid biosynthesis, and ultimately they likewise increase the transepidermal water loss. A long-lasting barrier weakness in turn makes skin that is per se healthy, more sensitive, and in individual cases may contribute to the development of eczematous processes in the diseased skin.
The effect of ointments and creams on the barrier function and hydration of the horny layer does not normally comprise a restoration or strengthening of the physico-chemical properties of the lamellae from intercellular lipids. A substantial partial effect is based on the mere covering of the treated skin regions and on the resultant water collection in the subjacent horny layer. Co-applied hygroscopic substances bind the water, so that a measurable increase of the water content in the horny layer develops. However, it is relatively easy to remove this merely physical barrier again. After the product is discontinued, the skin will return very rapidly to its condition before the start of the treatment. Moreover, the effect of skin care in the case of a regular treatment may subside, so that finally the status quo is again reached even during treatment. In the case of certain products, after their use is discontinued, the condition of the skin deteriorates, possibly temporarily. Thus, a long-lasting effect of the product is not normally achieved, or achieved only to a limited extent.
To assist the deficient skin in its natural regeneration, and to strengthen its physiological function, it has recently become more and more common to add topical preparations to the mixtures of intercellular lipids, which are to be used by the skin for rebuilding its natural barrier. However, these lipids, in particular the ceramides, are very expensive raw materials that are difficult to formulate. In addition, their effect is mostly much smaller than hoped for.
It is desirable to find ways of avoiding the disadvantages of the prior art. In particular, it is would be advantageous for the effect of skin care products to be physiological, fast, and long-lasting.
Skin care as intended by the present invention includes primarily that the natural function of the skin as a barrier against environmental influences (for example, dirt, chemicals, microorganisms) and against the loss of endogenous substances (for example, water, lipids, electrolytes) is strengthened or restored.
Products for the care, treatment, and cleansing of dry and stressed skin are known per se. However, their contribution to the regeneration of a physiologically intact, hydrated and smooth horny layer is limited in terms of scope and time.
The action of ointments and creams on the barrier function and the hydration of the horny layer is based substantially on the coverage (occlusion) of the treated skin regions. The ointment or cream represents as it were a (second) artificial barrier, which is intended to prevent a loss of water by the skin. Accordingly, this physical barrier is again easy to remove—for example, with cleansing agents—so that the original, impaired condition is reestablished. Moreover, the effect of the skin care may subside in the case of a regular treatment. After the product application is discontinued, the skin returns again very quickly to its condition before the start of the treatment. In the case of certain products, the condition of the skin sometimes even deteriorates temporarily. Thus, a long-lasting effect of the product is not achieved, or only achieved to a limited extent.
The effect of some pharmaceutical preparations on the barrier function of the skin even comprises a selective barrier damage, which is intended to make it possible for active substances to penetrate into the skin or through the skin into the body. In this regard, an impaired appearance of the skin as a side effect is partially accepted.
The effect of skin care cleansing products comprises in essence an efficient regreasing with sebum lipid-like substances. As a result of simultaneously reducing the surfactant content of such preparations, it is possible to further limit the damage to the horny layer barrier.
However, in the prior art there is a lack of preparations which positively influence the barrier function and the hydration of the horny layer, and strengthen or even restore the physico-chemical properties of the horny layer and in particular of the lamellae of intercellular lipids.
It would be advantageous to eliminate the disadvantages of the prior art. In particular, it would be advantageous to have available preparations for skin care and preparations for cleansing the skin which maintain or restore the barrier properties of the skin, particularly when the natural regeneration of the skin is insufficient. Furthermore, these preparations should be suitable for the treatment and prophylaxis of secondary damage from the drying out of the skin, for example, fissures or inflammatory or allergic processes, or even neurodermatitis. It also is desirable to have available stable, skin care cosmetic and/or dermatological agents, which protect the skin against environmental influences, such as sun and wind. In particular, it is desired that the effect of the preparation be physiological, fast, and long-lasting.
The present invention furthermore relates to preparations with extremely low so-called “stinging potential.” A neurosensory phenomenon called “stinging” (sting=injure, burn, hurt) can be observed in people with sensitive, susceptible or vulnerable skin. This “sensitive skin” differs in principle from “dry skin” with thickened and hardened horny layers.
Typical reactions of “stinging” on sensitive skin are reddening, tightening and burning of the skin and itching.
Itching of atopic skin and itching with skin diseases are to be regarded as neurosensory phenomena.
“Stinging” phenomena can be regarded as disturbances that can be treated cosmetically. Severe itching, on the other hand, especially severe itching of the skin which occurs with atopy, can also be described as a more serious dermatological disorder.
Typical troublesome neurosensory phenomena associated with the terms “stinging” or “sensitive skin” are reddening of the skin, tingling, prickling, tightening and burning of the skin and itching. These phenomena can be caused by stimulating environmental conditions, for example massage, action of surfactants, the influence of weather, such as sun, cold, dryness, and also damp heat, radiant heat and UV radiation, for example from the sun.
In “Journal of the Society of Cosmetic Chemists” 28, pages 197-209 (May 1977), the entire disclosure whereof is incorporated by reference herein, P. J. Frosch and A. M. Kligman describe a method for estimating the “stinging potential” of topically administered substances. Lactic acid and pyruvic acid, for example, are employed as positives in this method. During measurement by this method, however, amino acids, in particular glycine, were also identified as substances which exert a neurosensory action (such substances are called “stingers”).
According to knowledge to date, such sensitivity towards quite specific substances occurs differently in individuals. This means that a person that experiences “stinging effects” on contact with a substance will with a high probability experience it repeatedly on any further contact. However, contact with other “stingers” can just as easily proceed without any reaction.
The problem of sensitive skin affects a growing number of adults and children. Sensitive skin describes a combination of different symptoms, such as hyperreactive and intolerant skin. Atopic skin can also be included under this term. These skin conditions are often referred to by those affected, not quite correctly, as “allergic” skin. Although an allergic disorder can result in symptoms of sensitive skin, the “sensitive skin” phenomenon is not limited to allergy sufferers.
Many more or less sensitive people also suffer erythematous skin symptoms on using some deodorant or antiperspirant preparations.
Erythematous skin symptoms also occur as concomitant symptoms with certain skin diseases or irregularities. The typical skin rash with the clinical picture of acne, for example, is regularly reddened to a greater or lesser degree.
It would be advantageous to have available active substances and preparations comprising such active substances for the cosmetic and dermatological treatment and/or prophylaxis of erythematous, inflammatory, allergic or autoimmune-reactive symptoms, in particular dermatoses, and also the clinical picture of “stinging”.
It would also be advantageous to have available active substances and preparations comprising such active substances which can be used for the immuno-stimulation of the skin, and here advantageously also for immuno-stimulation in the context of an action that promotes wound healing.
The present invention relates, inter alia, to cosmetic and dermatological preparations for the prophylaxis and treatment of cosmetic or dermatological skin alterations, such as, e.g., undesirable pigmentation, e.g., local hyperpigmentation and abnormal pigmentation (e.g., moles, freckles), but also for the purely cosmetic lightening of larger skin areas that are per se appropriately pigmented for the individual skin type.
Pigmentation of the skin is due to melanocytes, which are found in the bottom layer of the epidermis, the basal stratum, next to the basal cells, which—depending on skin type—are present as pigment-forming cells either individually or in relatively large numbers. Melanocytes contain melanosomes as characteristic cell organelles, which produce more melanin when stimulated by UV radiation. The melanin is transported into the keratinocytes and causes more or less pronounced brownish or brown skin coloring.
Melanin is formed as the final stage in an oxidation process, in which tyrosine, with the aid of the enzyme tyrosinase, is converted to melanin via 3,4-dihydroxyphenyl alanine (dopa), dopa-quinone, leucodopachrome, dopachrome, 5,6-dihydroxyindol and indole-5,6-quinone.
Problems with hyperpigmentation of the skin have various causes and/or are side effects of many biological processes, e.g., UV radiation (e.g. freckles, ephelides), genetic disposition, defective pigmentation of the skin and/or scarring during the healing of wounds, or skin aging (e.g. lentigines seniles).
Active substances and preparations are known which counteract skin pigmentation. Those in practical use, in addition to 8-hexadecene-1,16-dicarboxylic acid, are essentially preparations based on hydroquinone, which however on the one hand only begin to show an effect after several weeks of use while on the other hand their use over a very long period is not always safe for toxicological reasons. The inhibition of tyrosinase with substances such as koji acid, ascorbic acid, azelaic acid and their derivatives is also common, but exhibits cosmetic and dermatological disadvantages.
Another goal of skin care is to compensate for the loss by the skin of sebum and water caused by daily washing. This is particularly important if the natural regeneration ability is inadequate. Furthermore, skin care products should protect against environmental influences, in particular against sun and wind, and delay skin aging.
Chronological skin aging is caused, for example, by endogenous, genetically determined factors. The following structural damage and functional disorders, which can also fall under the term “senile xerosis”, result, for example, in the epidermis and dermis as a result of aging:                a) dryness, roughness and formation of dryness wrinkles;        b) itching; and        c) reduced regreasing by sebaceous glands (e.g. after washing).        
Exogenous factors, such as UV light and chemical noxae, can have a cumulative effect and, for example, accelerate or supplement the endogenous aging processes. In the epidermis and dermis, for example, the following structural damage and functional disorders appear in the skin as a result of exogenous factors; these go beyond the extent and quality of the damage in the case of chronological aging:                d) visible vascular dilation (telangiectases, couperosis);        e) flaccidity and formation of wrinkles;        f) local hyperpigmentation, hypopigmentation and abnormal pigmentation (e.g. age spots); and        g) increased susceptibility to mechanical stress (e.g. cracking).        
The present invention also relates to products for the care of naturally aged skin, and to the treatment of the damage caused by photoaging, in particular of the phenomena listed under a) through g).
Products for the care of aged skin are known per se. They contain, for example, niacinamide, retinoids (vitamin A acid and/or derivatives thereof) or vitamin A and/or derivatives thereof. The extent of their effect on structural damage is, however, limited. Furthermore, in product development there are considerable difficulties in stabilizing the active ingredients to an adequate extent against oxidative decay. The use of products comprising vitamin A acid, moreover, often causes severe erythematous skin irritations. Retinoids can therefore only be used in low concentrations.
The present invention also relates to cosmetic preparations which provide effective protection against harmful oxidation processes in the skin, and also for the protection of cosmetic preparations themselves or the protection of the constituents of cosmetic preparations against harmful oxidation processes.
The present invention further relates to antioxidants, preferably those used in cosmetic or dermatological skin care preparations. In particular, the present invention also relates to cosmetic and dermatological preparations that comprise such antioxidants. In a preferred aspect, the present invention relates to cosmetic and dermatological preparations for the prophylaxis and treatment of cosmetic and dermatological skin changes, such as, for example, skin aging, in particular skin aging caused by oxidative processes.
Furthermore, the present invention relates to active substances and preparations comprising such active substances for the cosmetic and dermatological treatment or prophylaxis of erythematous, inflammatory, allergic or autoimmune-reactive symptoms, in particular dermatoses.
In a further advantageous aspect, the present invention relates to active ingredient combinations and preparations which serve for the prophylaxis and treatment of light-sensitive skin, in particular of photodermatoses.
The harmful effect of the ultraviolet part of solar radiation on the skin is generally known. Whereas rays with a wavelength of less than about 290 nm (the so-called UVC range) are absorbed by the ozone layer in the earth's atmosphere, rays in the range between about 290 nm and about 320 nm, the so-called UVB range, cause erythema, simple sunburn or even burns of greater or lesser severity. A maximum erythema activity of sunlight is indicated to occur within the relatively narrow range around 308 nm.
Numerous compounds are known for protecting against UVB radiation; these are derivatives of 3-benzylidenecamphor, of 4-aminobenzoic acid, of cinnamic acid, of salicylic acid, of benzophenone and also of 2-phenylbenzimidazole.
It is also desirable to have available filter substances for the range between about 320 nm and about 400 nm, the so-called UVA range, since the corresponding rays can cause reactions in cases of photosensitive skin. It has been found that UVA radiation results in damage of the elastic and collagenous fibers of connective tissue, which leads to premature aging of the skin, and is to be regarded as a cause of numerous phototoxic and photoallergic reactions. The harmful effect of UVB radiation can be intensified by UVA radiation.
To protect against rays of the UVA range, certain derivatives of dibenzoylmethane are therefore used. However, the photostability of these derivatives is inadequate (Int. J. Cosm. Science 10, 53 (1988), the entire disclosure whereof is incorporated by reference herein).
UV radiation can, however, also lead to photochemical reactions, in which case the photochemical reaction products interfere with the skin metabolism.
Such photochemical reaction products are predominantly free radical compounds, for example hydroxyl radicals and singlet oxygen. Undefined free radical photoproducts which form in the skin itself can also display uncontrolled secondary reactions because of their high reactivity. However, singlet oxygen, a non-free radical excited state of the oxygen molecule, can also be formed during UV irradiation, as can short-lived epoxides and many others. Singlet oxygen, for example, differs from normal triplet oxygen (free radical ground state) by virtue of its increased reactivity. However, excited, reactive (free radical) triplet states of the oxygen molecule also exist.
UV radiation is also a type of ionizing radiation. There is therefore the risk that ionic species will also form during UV exposure, which for their part are able to interfere oxidatively with the biochemical processes.
In order to prevent these reactions, additional antioxidants and/or free radical scavengers can be incorporated into cosmetic or dermatological formulations.
It has already been proposed to use vitamin E, a substance with known antioxidant action, in sunscreen formulations, although, here too, the effect achieved falls far short of expectations.
It is desirable to be able to provide cosmetically, dermatologically and pharmaceutically active substances and preparations, and sunscreen formulations which serve for the prophylaxis and treatment of photosensitive skin, in particular photodermatoses, preferably PLD.
Other names for polymorphous light dermatosis are PLD, PLE, Mallorca acne and a large number of other names, as given in the literature (e.g. A. Voelckel et al, Zentralblatt Haut- and Geschlechtskrankheiten (1989), 156, p. 2, the entire disclosure whereof is incorporated by reference herein).
Antioxidants are mainly used as substances which protect against the deterioration of the preparations in which they are present. Nevertheless, it is known that in human or animal skin undesired oxidation processes may occur as well. Such processes play an important role in skin aging.
The article “Skin Diseases Associated with Oxidative Injury” in “Oxidative Stress in Dermatology”, p. 323 ff. (Marcel Decker Inc., New York, Basel, Hong Kong, Editor: Jürgen Fuchs, Frankfurt, and Lester Packer, Berkeley/Calif.), the entire disclosure whereof is incorporated by reference herein, discusses oxidative skin damage and its more direct causes.
Also for the reason of preventing such reactions, antioxidants and/or free radical scavengers can be additionally incorporated into cosmetic or dermatological formulations.
A number of antioxidants and free radical scavengers are known. For example U.S. Pat. Nos. 4,144,325 and 4,248,861, the entire disclosures whereof are incorporated by reference herein, and numerous other documents have already proposed the use of vitamin E, a substance with known antioxidant activity in sunscreen formulations, although here, too, the effect achieved falls far short of the desired effect.
The anti-inflammatory effect of licochalcone A is known per se. To obtain this effect in topical formulations, however, the solubility of licochalcone A in the vehicle and a sufficient dermal bioavailability are important prerequisites. However, licochalcone A is a poorly soluble substance which can crystallize during storage and processing. This crystallization tendency is a great problem, since substance crystals can lead to an uncosmetic appearance, formula instabilities and/or loss of effectiveness.
It is therefore desirable to increase the solubility of licochalcone A and thus its biological availability.
It would be advantageous to find ways of avoiding the disadvantages of the prior art. In particular, the effect of eliminating the damage associated with the endogenous, chronological and exogenous aging of the skin and the prophylaxis should be lasting, sustained and without the risk of side effects.